Radiation therapy is a powerful tool for the treatment of a wide range of cancers. Since radiation must penetrate the skin to reach the tumor site, the skin receives dose-dependent damage during radiation treatment. The skin is susceptible to radiation damage, because it is a continuously renewing organ, which contains rapidly proliferating and maturing cells, with basal keratinocytes, hair follicle stem cells and melanocytes being very radiosensitive. See, e.g., Ryan, Ionizing radiation: the good, the bad, and the ugly, J Invest Dermatol, 132:985-93 (2012). The most sensitive skin areas are the anterior of the neck, extremities, chest, abdomen and face, along with the hair follicles on the scalp and breast tissue. See, e.g., McQuestion, Evidence-based skin care management in radiation therapy: clinical update, Semin Oncol Nurs, 27:e1-17 (2011). The skin injury manifests itself as radiation-induced dermatitis in approximately 95% of patients receiving radiotherapy, with the injury ranging from mild erythema to moist desquamation and skin ulceration. See, e.g., Brown et al., Acute and chronic radiation injury, J Vasc Surg, 53:15S (2011). Approximately 20-25% of patients receiving radiotherapy experience moist desquamation and ulceration. See, e.g., Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck, Ann Oncol, 19:142 (2008). Radiation dermatitis has a profound impact on the quality of a patient's life, due to pain, itching, and poor aesthetic appearance. In addition it may be the cause of premature interruption of radiation therapy, resulting in inadequate disease treatment. See, e.g., Isomura et al., IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis, Clin Cancer Res, 14:6683 (2008). In the long term, skin wounds can reappear due to abnormal pathological changes, such as excessive fibrosis that can occur during the initial phases of the healing process. See, e.g., Olascoaga et al., Wound healing in radiated skin: pathophysiology and treatment options, Int Would J, 5:246-57 (2008).
Radiation-induced dermatitis is primarily due to cellular oxidative stress by generation of reactive oxygen species (ROS) such as peroxides and superoxide, as well as the highly reactive hydroxyl and hydrogen radicals. See, e.g., Niwa et al., Protein oxidation damage in the stratum corneum: Evidence for a link between environmental oxidants and the changing prevalence and nature of atopic dermatitis in Japan, Br J Dermatol, 149:248-254 (2003). Furthermore, proinflammatory processes such as cytokine release and inflammatory cell infiltration lead to further ROS generation, damage and disease pathology. Rosenthal et al., Salen Mn complexes mitigate radiation injury in normal tissues, Anticancer Agents Med Chem, 11:359-72 (2011).
The most common strategy for preventing and minimizing radiation-induced dermatitis involves simple moisturization of the irradiated area and using a mild soap to keep the area clean. See, e.g., Maddocks-Jennings et al., Novel approaches to radiotherapy-induced skin reactions: a literature review, Complement Ther Clin Pract, 11:224-31 (2005). However, all of the currently used treatment regimens lack clinically significant efficacy. For example, the use of aloe vera gel, hyaluronidase-based creams or sucralfate creams, did not result in significant improvements in dermatitis scoring. See, e.g., Salvo et al., Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature, Curr Oncol, 17:94-112 (2010). As such, there remains a need for an effective pharmacologic treatment for dermatitis, in particular radiation-induced dermatitis.
Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. See, e.g., Graça Raposo and Willem Stoorvogel, Extracellular Vesicles: Exosomes, Microvesicles, and Friends, The Journal of Cell Biology, Vol. 200, No. 4, 373-383 (2013). WO 2014/028493 describes exosomes derived cardiosphere-derived cells (CDCs) and their therapeutic utility for the repair or regeneration of damaged or diseased cells or tissue, e.g., damaged cardiac tissue. US 2012/0315252 in turn describes CDCs, their derivation from cardiospheres, and their therapeutic utility for increasing the function of a damaged or diseased heart of a mammal. WO 2005/012510 in turn describes cardiospheres, their derivation from human or animal cardiac tissue biopsy samples, and their therapeutic utility in cell transplantation and functional repair of the myocardium or other organs.